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RNA Technologies in Cardiovascular Medicine and Research pp 209–231Cite as

Applications of Ribozymes and Pyrrole–Imidazole Polyamides for Cardiovascular and Renal Diseases

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Abstract

Ribozymes are RNA molecules that cleave a phosphodiester bond in the appropriate target RNAs in a sequence-specific manner, thereby inhibiting the expression of specific gene products. Ribozymes have progressed from objects of scientific study to potential therapeutic agents for treatment of both acquired and inherited diseases. We have developed ribozymes for therapy of arterial proliferative diseases, such as coronary artery restenosis after angioplasty or stent implantation, hypertensive vascular diseases, atherosclerosis, and progressive renal diseases. We designed nuclease resistant chimeric DNA–RNA hammerhead ribozymes targeting platelet-derived growth factor (PDGF) A-chain and transforming growth factor (TGF)-β1, which effectively and specifically inhibited the exaggerated growth of vascular smooth muscle cells from hypertensive rats in vitro, the arterial stenosis after injury and the renal sclerosis in hypertensive rats in vivo. Pyrrole-imidazole (PI) polyamides are novel gene-silencing compounds, which bind to minor groove of double-strand DNA in the sequence-specific manner to suppress target gene expression. We have developed PI polyamide targeting TGF-β1 promoter and lectin-like oxidized low density lipoprotein receptor-1 (LOX-1). The polyamide to TGF-β1 inhibited expression of TGF-β1 gene and protein in vitro and in vivo. Prolonged treatments with the polyamide to TGF-β1 markedly improved the progressive renal dysfunction without any side effects in hypertensive rats. PI polyamide to LOX-1 significantly suppressed the apoptosis of endothelial cells in vitro and the arterial stenosis after angioplasty in vivo. These findings suggest that ribozymes and PI polyamides will be effective gene suppressive agents for cardiovascular and renal diseases.

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Abbreviations

Ang II:

Angiotensin II

Im:

N-methylimidazole

LOX-1:

Lectin-like oxidized low-density lipoprotein receptor-1

PDGF:

Platelet-derived growth factor

PI:

Pyrrole-Imidazole

Py:

N-methylpyrrole

SHR:

Spontaneously hypertensive rats

siRNA:

Small interference RNA

TGF:

Transforming growth factor

VSMC:

Vascular smooth muscle cell

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Authors and Affiliations

  1. Department of Medicine, Division of Nephrology and Endocrinology, Nihon University School of Medicine, Tokyo, Japan

    E. -H. Yao & N. Fukuda

  2. Advanced Research Institute of Science and Humanities, Nihon University School of Medicine, Tokyo, Japan

    N. Fukuda

Authors
  1. E. -H. Yao
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  2. N. Fukuda
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Correspondence to N. Fukuda .

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Editors and Affiliations

  1. Institute for Chemistry/Biochemistry, Free University of Berlin, Thielallee 63, 14195, Berlin, Germany

    Volker A. Erdmann

  2. Clinic for Cardiology and Pneumology Campus Benjamin Franklin, Charite University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany

    Wolfgang Poller

  3. Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Noskowskiego 12, 61-704, Poznan, Poland

    Jan Barciszewski

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Yao, E.H., Fukuda, N. (2008). Applications of Ribozymes and Pyrrole–Imidazole Polyamides for Cardiovascular and Renal Diseases. In: Erdmann, V.A., Poller, W., Barciszewski, J. (eds) RNA Technologies in Cardiovascular Medicine and Research. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-78709-9_11

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